BGB-58067, a brain-penetrative MTA-cooperative PRMT5 inhibitor, demonstrates promising anti-tumor activity and favorable selectivity in tumors with MTAP-deletion

PRMT5 was identified as a synthetic lethal target for cancers harboring homozygous deletion of the MTAP gene. MTA was found to accumulate in tumor cells with MTAP-deletion, which inhibited PRMT5 enzymatic activity and increased susceptibility to additional PRMT5 depletion. The homozygous MTAP-deletion was observed in 15% of all tumor types. MTA-cooperative PRMT5 inhibitors have been developed as potential antitumor therapies in tumor types with MTAP-deletion as they selectively bind and stabilize the catalytically inactive PRMT5/MTA complex to inhibit PRMT5 enzymatic activity. BGB-58067 is a highly potent and selective MTA-cooperative PRMT5 inhibitor with good brain penetration potential. BGB-58067 is highly selective for PRMT5 over other methyltransferase family members. It shows strong killing potency and good selectivity (>50-fold) in the cancer cell lines panel with MTAP-deletion over cell lines with MTAP-WT. BGB-58067 very weakly hits on normal hematological cells and demonstrates preferable selectivity (>30-fold) than competitors. BGB-58067 induces robust anti-tumor activity in multiple cell line-derived xenograft models. BGB-58067 demonstrates desirable pharmacokinetics properties and low DDI risk. It exhibits excellent unbound brain-to-plasma partition coefficient to support robust intracranial anti-tumor activity. BGB-58067 shows favorable nonclinical safety profile in the GLP studies, as well as good selectivity in an in vitro SafetyScreen87-off target profiling study. In conclusion, BGB-58067 demonstrates robust potency and selectivity, providing a favorable safety margin for patients, with high potential for the treatment of brain tumors and brain metastases.